Comparative safety and efficacy of vasopressors for mortality in septic shock: A network meta-analysis

© 2015, © The Intensive Care Society 2015.Introduction: Septic shock is a life-threatening condition requiring vasopressor agents to support the circulatory system. Several agents exist with choice typically guided by the specific clinical scenario. We used a network meta-analysis approach to rate the comparative efficacy and safety of vasopressors for mortality and arrhythmia incidence in septic shock patients. Methods: We performed a comprehensive electronic database search including Medline, Embase, Science Citation Index Expanded and the Cochrane database. Randomised trials investigating vasopressor agents in septic shock patients and specifically assessing 28-day mortality or arrhythmia incidence were included. A Bayesian network meta-analysis was performed using Markov chain Monte Carlo methods. Results: Thirteen trials of low to moderate risk of bias in which 3146 patients were randomised were included. There was no pairwise evidence to suggest one agent was superior over another for mortality. In the network meta-analysis, vasopressin was significantly superior to dopamine (OR 0.68 (95% CI 0.5 to 0.94)) for mortality. For arrhythmia incidence, standard pairwise meta-analyses confirmed that dopamine led to a higher incidence of arrhythmias than norepinephrine (OR 2.69 (95% CI 2.08 to 3.47)). In the network meta-analysis, there was no evidence of superiority of one agent over another. Conclusions: In this network meta-analysis, vasopressin was superior to dopamine for 28-day mortality in septic shock. Existing pairwise information supports the use of norepinephrine over dopamine. Our findings suggest that dopamine should be avoided in patients with septic shock and that other vasopressor agents should continue to be based on existing guidelines and clinical judgement of the specific presentation of the patient

Knowledge of Driving Vehicle Licensing Agency guidelines among NHS doctors:A multicentre observational study

Objectives: Over half of the UK population holds a driver's licence. The DVLA have produced guidelines to ensure drivers with medical conditions drive safely. Doctors should ensure that patients are given appropriate information and advice if they have a medical condition affecting their driving. We sought to evaluate doctors' knowledge of DVLA guidelines. Design: A 25-point questionnaire was designed from DVLA guidelines (‘The DVLA Questionnaire’). Five questions were included for each of neurology, cardiology, drug and alcohol abuse, visual, and respiratory disorders. Setting: Ealing Hospital, Northwick Park Hospital, Watford General Hospital, Norfolk and Norwich University Hospital and Leeds Teaching Hospitals Trust. Participants: 140 UK doctors. Main outcome measures: Questionnaire scores assessing knowledge of DVLA guidelines in five specialty areas. Results: The median overall questionnaire score was 28%, interquartile range 20–36% and range 0–100% [Watford 28%, Leeds 30%, Norfolk and Norwich 36%, Ealing 30%, Northwick Park 28%]. There were no significant differences between the scores for each centre (p = 0.1332), Mean scores for specialty areas were: neurology 33.1%, standard deviation 22.1; cardiology 35.6%, standard deviation 26.9; drug and alcohol abuse 30.6%, standard deviation 23.8; visual disorders 33.9%, standard deviation 23.5 and respiratory disorders 20.3%, standard deviation 24.8; overall score 30.7%. There was no significant difference between the scores of the specialty areas (p = 0.4060). Conclusions: Knowledge of DVLA guidelines in our cohort was low. There is a need for increased awareness among hospital doctors through focused education on driving restrictions for common medical conditions. Improving physician knowledge in this area may help optimise patient safety

Trends in Mortality from Ischaemic Heart Disease and Cerebrovascular Disease in Europe: 1980-2009.

Background— Trends in cardiovascular mortality across Europe demonstrate significant geographical variation, and an understanding of these trends has a central role in global public health. Methods and Results— Ischemic heart disease and cerebrovascular disease age-standardized death rates (as per International Classification of Diseases , ninth and tenth revisions) were collated from the World Health Organization mortality database for member states of the European Union. Trends were characterized by using Joinpoint regression analysis. An overall trend for reduction in ischemic heart disease mortality was observed, most pronounced in Western Europe (&gt;60% for the Netherlands, United Kingdom, and Ireland) for both sexes from 1980 to 2009. Eastern European states, Romania, Croatia, and Slovakia, had modest mortality reductions. Most recently (2009), Lithuania had the highest mortality for males and females (318.1/100 000 and 166.1/100 000, respectively), followed by Latvia and Slovakia. France had the lowest mortality: 39.8/100 000 for males and 14.7/100 000 for females. Analysis of cerebrovascular disease mortality revealed that Austria had the largest reduction for both sexes (76.8% males, 76.5% females) from 1980 to 2009. The smallest improvement over this period was seen in Lithuania, Poland, and Cyprus (–5% to +20% approximately). France has the lowest present-day cerebrovascular disease mortality for both males and females (23.9/100 000 and 17.3/100 000, respectively). Conclusions— There is a growing disparity in cardiovascular mortality between Western and Eastern Europe, for which diverse explanations are discussed. The need for population-wide health promotion and primary prevention policies is emphasized. </jats:sec

Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms

Research on iRHOM2 in the Kelsell group is funded by an MRC project grant, a MRC Clinical Fellowship (to TM) and a Cancer Research UK program grant

Pathogenic FAM83g palmoplantar keratoderma mutations inhibit the PAWS1::Ck1α association and attenuate wnt signalling

Background: Two recessive mutations in the FAM83G gene, causing A34E and R52P amino acid substitutions in the DUF1669 domain of the PAWS1 protein, are associated with palmoplantar keratoderma (PPK) in humans and dogs respectively. We have previously reported that PAWS1 associates with the Ser/Thr protein kinase CK1α through the DUF1669 domain to mediate canonical Wnt signalling. Methods: Co-immunoprecipitation was used to investigate possible changes to PAWS1 interactors caused by the mutations. We also compared the stability of wild-type and mutant PAWS1 in cycloheximide-treated cells. Effects on Wnt signalling were determined using the TOPflash luciferase reporter assay in U2OS cells expressing PAWS1 mutant proteins. The ability of PAWS1 to induce axis duplication in Xenopus embryos was also tested. Finally, we knocked-in the A34E mutation at the native gene locus and measured Wnt-induced AXIN2 gene expression by RT-qPCR. Results: We show that these PAWS1 A34E and PAWS1 R52P mutants fail to interact with CK1α but, like the wild-type protein, do interact with CD2AP and SMAD1. Like cells carrying a PAWS1 F296A mutation, which also abolishes CK1α binding, cells carrying the A34E and R52P mutants respond poorly to Wnt signalling to an extent resembling that observed in FAM83G gene knockout cells. Consistent with this observation, these mutants, in contrast to the wild-type protein, fail to induce axis duplication in Xenopus embryos. We also found that the A34E and R52P mutant proteins are less abundant than the native protein and appear to be less stable, both when overexpressed in FAM83G-knockout cells and when knocked-in at the native FAM83G locus. Ala 34 of PAWS1 is conserved in all FAM83 proteins and mutating the equivalent residue in FAM83H (A31E) also abolishes interaction with CK1 isoforms. Conclusions: We propose that mutations in PAWS1 cause PPK pathogenesis through disruption of the CK1α interaction and attenuation of Wnt signalling. </p

Discordance in glycemic categories and regression to normality at baseline in 10,000 people in a Type 2 diabetes prevention trial

The world diabetes population quadrupled between 1980 and 2014 to 422 million and the enormous impact of Type 2 diabetes is recognised by the recent creation of national Type 2 diabetes prevention programmes. There is uncertainty about how to correctly risk stratify people for entry into prevention programmes, how combinations of multiple ‘at high risk’ glycemic categories predict outcome, and how the large recently defined ‘at risk’ population based on an elevated glycosylated haemoglobin (HbA1c) should be managed. We identified all 141,973 people at highest risk of diabetes in our population, and screened 10,000 of these with paired fasting plasma glucose and HbA1c for randomisation into a very large Type 2 diabetes prevention trial. Baseline discordance rate between highest risk categories was 45.6 %, and 21.3 - 37.0 % of highest risk glycaemic categories regressed to normality between paired baseline measurements (median 40 days apart). Accurate risk stratification using both fasting plasma glucose and HbA1c data, the use of paired baseline data, and awareness of diagnostic imprecision at diagnostic thresholds would avoid substantial overestimation of the true risk of Type 2 diabetes and the potential benefits (or otherwise) of intervention, in high risk subjects entering prevention trials and programmes

Financial performance of English NHS trusts and variation in clinical outcomes: a longitudinal observational study

OBJECTIVES: To examine the association between financial performance as measured by operating margin (surplus/deficit as a proportion of turnover) and clinical outcomes in English National Health Service (NHS) trusts. SETTING: Longitudinal, observational study in 149 acute NHS trusts in England between the financial years 2011 and 2016. PARTICIPANTS: Our analysis focused on outcomes at individual NHS Trust-level (composed of one or more acute hospitals). PRIMARY AND SECONDARY OUTCOMES: Outcome measures included readmissions, inpatient satisfaction score and the following process measures: emergency department (Accident and Emergency (A&E)) waiting time targets, cancer referral and treatment targets and delayed transfers of care (DTOCs). RESULTS: There was a progressive increase in the proportion of trusts in financial deficit: 22% in 2011, 27% in 2012, 28% in 2013, 51% in 2014, 68% in 2015 and 91% in 2016. In linear regression analyses, there was no significant association between operating margin and clinical outcomes (readmission rate or inpatient satisfaction score). There was, however, a significant association between operating margin and process measures (DTOCs, A&E breaches and cancer waiting time targets). Between the best and worst financially performing Trusts, there was an approximately 2-fold increase in A&E breaches and DTOCs overall although this variation decreased over the 6 years. Between the best and worst performing trusts on cancer targets, the magnitude of difference was smaller (1.16 and 1.15-fold), although the variation slowly rose during the 6 years. CONCLUSIONS: Operating margins in English NHS trusts progressively worsened during 2011-2016, and this change was associated with poorer performance on several process measures but not with hospital readmissions or inpatient satisfaction. Significant variation exists between the best and worst financially performing Trusts. Further research is needed to examine the causal nature of relationships between financial performance, process measures and outcomes

What's New After NICE Acne Guidelines

INTRODUCTION: Acne remains one of the most common inflammatory dermatoses seen worldwide. There are significant challenges when managing acne relating to a variety of factors, including (1) lack of consensus on the use of the numerous available grading systems and outcome measures, (2) appreciation of the numerous areas that relate to severity, (3) the chronic nature of acne which requires a longitudinal approach to management (including both facial and truncal disease), and (4) the need to target acne early to avoid physical and psychosocial scarring. Consideration of these aspects when managing acne should result in improved outcomes. Acne guidelines review the available evidence based on robust clinical trials and are usually supplemented with some expert opinion when evidence is not available.METHODS: In this paper, the UK Acne Working Group reflects on the latest National Institute for Health and Care Excellence (NICE) acne guidelines with a goal of providing additional practical insights.CONCLUSION: The group have identified areas where new evidence has now become available since the formulation of the NICE acne guidelines. This publication considers newly approved acne medications in the UK, guidance on assessing acne severity, approaches to managing truncal acne, acne sequelae, and adult female acne with hormonal therapies.</p